Novel benzoylphenylacetic acid esters in the treatment of pain and inflammation

ABSTRACT

P and Q being alkyl of 1 to 5 carbon atoms and the two benzene rings may be optionally substituted with at least one member of the group consisting of chlorine, fluorine, bromine, trifluoromethyl and alkyl and alkoxy and alkylthio of 1 to 7 carbon atoms, intermediates and process for their preparation and their use as analgesics and antiinflammatory agents.   WHEREIN R is selected from the group consisting of hydrogen and alkyl of 1 to 7 carbon atoms, R1 and R2 are hydrogen or taken together are   Racemates and optically active isomers of benzoylphenyl-acetic acid esters of the formula

United States Patent 11 1 Allais et al.

1 Aug. 13, 1974 1 NOVEL BENZOYLPHENYLACETIC ACID ESTERS IN THE TREATMENTOF PAIN AND INFLAMMATION [76] Inventors: Andr Allais, Les Lilas; JeanMeier, Coeuilly-Champigny; Jacques Dub, Eaubonne, all of France [22]Filed: Apr. 2, 1973 [21] Appl. No.: 346,770

Related US. Application Data [62] Division of Ser. No. 133,429, April12, 1971, Pat.

[30] Foreign Application Priority Data OTHER PUBLICATIONS Chem. Abst.,Vol. 70, C01. 77597C (1969).

Primary Examiner-Stanley J Friedman Attorney, Agent, or Firm-Charles A.Muserlian [57] ABSTRACT Racemates and optically active isomers ofbenzoylphenyl-acetic acid esters of the formula ll 0R1 OR: Q 1

wherein R is selected from the group consisting of hydrogen and alkyl of1 to 7 carbon atoms, R and R are hydrogen or taken together are P and Qbeing alkyl of l to 5 carbon atoms and the two benzene rings may beoptionally substituted with at least one member of the group consistingof chlorine, fluorine, bromine. trifluoromethyl and alkyl and alkoxy andalkylt'hio of 1 to 7 carbon atoms, intermediates and process for theirpreparation and their use as analgesics and antiinflammatory agents.

5 Claims, No Drawings NOVEL BENZOYLPHENYLACETIC ACID ESTERS IN THETREATMENT OF PAIN AND INFLAMMATION PRIOR APPLICATION This application isa division of copending commonly assigned US. application Ser. No.133,429, filed Apr. 12, 1971, now US. Pat. No. 3,741,988.

STATE OF THE ART The literature describes certain derivatives ofmetabenzolyphenylacetic acids. French Pats. No. 1,516,775 and 1,546,478and French Pat. BSM 6444 l M describe metabenzoylphenyl acetic acidssubstituted or unsubstituted in one or the other aromatic ring or in theside chain. Belgian Pat. No. 718,466 describes the acids and derivativesof the carboxylic acid group such as alkyl esters, aryl esters,aminoalkyl esters, amides and hydroxamic acids. These references teachthat the said compounds possess anti-inflammatory activity aboutequal tophenyl butazone and analgesic activity.

However, no one has described the exterification ofmetabenzoylphenylacetic acids with polyhydroxy alcohols ortheir blockedderivatives. Glycerin esters or their blocked derivatives have beendescribed for quinoleinic compounds in French Pat. No. 1,421,229

(oi-glycerin esters), in French Pat. BSM 5310 M (B-glyce'rin esters) andin French Pat. BSM 4775 M (blocked a-glycerin esters in form ofketonides).

OBJECTS OF THE INVENTION It is an object of the invention to provide thenovel esters of formula 1.

It is another object of the invention to provide novel intermediates andnovel process for the .preparation of THE lNVENTlON The novel compoundsof the invention are racemates and optically active isomers ofbenzoylphenylacetic acid esters of the formula u (hit-C o0 Cllr-Cll-CII:

om 0R:

wherein R is selected from the group consisting of hydrogen and alkyl of1 to 7 carbon atoms, R, and R are hydrogen or taken together are P and Qbeing alkyl of 1 to 5 carbon atoms and the two benzene rings may beoptionally substituted with at least one member of the group consistingof chlorine. fluorine, bromine, trifluoromethyl and alkyl and alkoxy andalkylthio of 1 to 7 carbon atoms.

Preferred compounds of formula I are [4'-(2,2'- dimethyl-l',3'-dioxolane)] methanol esters of 3-p-chlorobenzoylphenylacetic. acid,3-pchlorobenzoyl-2-methyl-phenylacetic acid and a-(3-pchlorobenzoylyphenyl)-propionic acids and the glycerin mono-esters of3-p-chlorobenzoylphenylacetic acid, 3-p-chlorobenzoyl Z-methyl-phenylacetic acid and a-( 3-p-chlorobenzoylphenyl)-propionic acid.

The novel process for the preparation of the compounds of formula Icomprises reacting an acid of the formula wherein P and 0 have the abovedefinition to obtain a corresponding ester of the formula which may bea-alkylated by treatment with a basic agent such as alkali metalhydrides, amides or dialkylamides then with alkylating derivative of thetype R'X, R" 50 R, ArSo R', and SO (OR) wherein R and R" are loweralkyl, X is halogen and Ar is an aromatic radical to form thecorresponding ester of the formula The compounds of formulae 1' and 1''can be hydrolyzed in the presence of an organic or mineral acid to formthe corresponding ester of the formula wherein R has the abovedefinition.

The treatment with the homologation agent and dioxolane-4-methanolpermits the direct conversion of the benzoic acid derivative to itshigher esterified homolog. The method of homologation is theAmdt-Eistert method consisting principally of treating the benzoic acidof formula ll with a chlorination agent to form the corresponding acidchloride which is then reacted with diazomethane to form the diazoketonewhich rearranges in the presence of a silver derivative such as silveroxide or silver benzoate with the last step being effected in thepresence of a dioxolane-4-methanol to obtain the ester of formula I.

The decomposition of the diazoketone is preferably effected with silverbenzoate in solution in a tertiary amine such as triethylamine and thediazoketone in solution in dioxolane-4-methanol of formula Ill..

The a-alkylation step is preferably effected by reacting the ester offormula I with a lithium dialkylamide such as lithium diethylamide in amixture of solvents with a strong dielectric constant such ashexametl'iylphosphortriamide and tetrahydrofuran and the reactionproduct is then reacted with an alkyl iodide. Other basic agents such assodium hydrideor sodium amide and other organic media suchas-dimethylformamide or an ether-benzene mixture may also be used.

The hydrolysis of the ester of formula I or I" may be effected with amineral acid such as hydrochloric acid, sulfuric acid, perchlor'icacid,boric acid, etc., or an or-' ganic acid such'as acetic acid,trichloroacetic acid, fora I. s 0 me acid, tnfluoroacetic acid, etc.

The substituted benzoic acids of formula ll used as the startingmaterials can be prepared the process of 1 Belgian Pat. No. 718,466 byhydrogenating m -nitrosired acid. The said processes can be used toprepareother compounds of formula II.

In a variation of the process to obtain an ester of formula l, theprocess comprises reacting a benzoic acid of the formula with anesterification agent an alkyl of 1 to 3 carbon atoms to form the esterof the formula CH-CDOAlk wherein R has the above meaning and Alk isalkyl of l to 3 carbon atoms, subjecting the said ester totransesterification in the presence of an alkaline agent with adioxolane-4-methanol of the formula wherein P and Q have the abovedefinitions to form the corresponding ester of the formula which ifdesired can be hydrolyzed with an organic or mineral acid to form thecorresponding polyol ester.

The alkaline agent for the transesterification is 'prefe rably analkali. metal such assodium, an alkali metal alcoholate such assodiumethylate, an alkali metal hydride or an alkali metal amide.The-preferred agent is sodium hydride. The acids for the hydrolysis maybe the same as discussed above. I

The acids of formula N can be prepared by a process whereinS-methyl-benzophenone is reacted with a brominating agent to form 3bromomethyl-benzophenone, the latter is reacted with an alkalimetalcyanide to form m-benzoylphenylacetonitrile which can be hydrolyzed tothe corresponding acid or reacted with an alk'ylating agent in in thepresence of sodium hydride to form a meta-benzoyl-aalkylphenylacetonitrile which is acid.

The novel anti-inflammatory and analgesic compositions of the inventionare comprised of an effective amount of at least one ester of formula Iand a pharmaceutical carrier. The compositions may be in the form ofinjectable solutions or suspensions in ampoules, mulform of tablets,coated tablets, gelules, sublingual tablets, 'syrups, emulsions,suppositories, granules, aromatic powders, creams, pomades, gels, dropsor powders.

The compositions usually contain 5 to 200mg of the active compound offormula I depending upon the specific compound and the method ofadministration. The compositions may also contain other activeprinciples such as spasmolytics, anti-coagulants, antipyretics orsedatives.

then hydrolyzed to the corresponding phenylacetic tiple dose flacons orautoinjectable syringes, or in the permits the reeducation of muscles.The compositions soothe aches, increase articular movements, increasethe rate of perimeter of step and struggle against ankylosis andinflammation The esters of formula I have a much higheranti-inflammatory activity than the corresponding free acids whilehaving the same degree of analgesic activity as the free acids.Notwithstanding the very sensible increase in the anti-inflammatoryactivity of the esters in relation to the corresponding acids, theulcergenic properties possessed by most antiinflammatory products is ofthe same or a lesser order resulting in an important improvement of themargin of safety. The analgesic properties of the ketonides of formula lare superior to known analgesics such as indomethacine, niflumic acid orphenylbutazone.

The novel method of the invention for relieving pain and inflammation inwarm-blooded animals comprises administering to warm-blooded animals aneffective amount of at least one compound of formula I. The compoundsmay be administered orally, transcutaneously, rectally, perlingually,topically or transmucously. The usual daily dose is 0.15 to I5 mg/kgdepending upon the compound and the method of administration.

In the following examples there are described several preferredembodiments to illustrate the invention. However, it should beunderstood that the invention is not intended to be limited to thespecific embodiments.

EXAMPLE I PREPARATION OF [4-(2', 2-dimethyl-1,3-

dioxolane)]methyl a-(3-p-chlorobenzoyl phenyl) propionate STEP A:3-p-chlorobenzoyl-benzonitrile 30 g of magnesium turnings in 400 cc ofether were heated to reflux and then a solution of 190 g ofpbromo-chloro-benzene in 600 cc of ether was added over one hour afterwhich the mixture was refluxed for 1 1e hours to obtain a solutiontitrating 0.77 mole of magnesium compound per liter. 31.4g of cadmiumchloride (dried at 140C) were added over minutes to 450 cc of the saidmagnesium solution at 15C and after stirring for 1 hour at roomtemperature the ether was eliminated by distillation while progressivelyreplacing the same with benzene to maintain a constant volume. Theresulting solution was cooled to 5 C and a solution of 54.5 g of3-cyano-benzoic acid chloride [Slotta et al., Ber., V0171 (1938),P.33541] in 300 cc of benzene was added thereto over minutes. Themixture was stirred for 15 hours at room temperature and then refluxedfor 3 hours. After cooling to 10 C, an aqueous solution of 2.5 percenthydrochloric acid was added thereto and the organic phase was decantedoff. The aqueous phase was extracted with methylene chloride and theorganic phases were combined, successively washed with aqueous 2Nhydrochloric acid solution, water, aqueous 2N sodium hydroxide solutionand water, dried, treated with activated carbon, stirred and filtered.The filtrate was evaporated to dryness under reduced pressure and theresidue was empasted with isopropyl ether and dried to obtain 47.5 g of3-pchlorobenzoyl-benzonitrile melting at 142C. A sample melted at 142C.

' of the product after crystallization from methanol Analysis: C H NClO;molecular weight 241.68

7zCl 14.67

Calculated:

Found:

As far as is known, this compound is not described in the literature.

STEP B: 3-p-chlorobenzoyl-benzoic acid 46.5g of 3-p-chlorobenzoylbenzonitrile were added I Analysis: C H C OK; molecular weight 260.63

7(Cl l3.60

Calculated: Found:

As far as is known, this compound is not described in the literature.

STEP C: [4'-(2,2'-dimethyl-l 3'-dioxolane] methyl 3-p-chloro benzoylphenyl acetate 47 g of 3-p-chloro benzoyl-benzoic acid were added to 470cc of thionyl chloride and the mixture was refluxed for 3 hours and thencooled to 20C. The mixture was concentrated to dryness by distillationunder reduced pressure to obtain a residue of 3-p-chlorobenzoyl-benzoicacid chloride which as far as is known is not described in theliterature.

54.8 gm of the said acid chloride were added to 500 cc of methylenechloride and after cooling to 5 C, 1.5 liters of a solution of 15.2g perliter of diazomethane in methylene chloride was added thereto over 20minutes.

The mixture was stirred for 15 hours at 20C and was concentrated todryness by distillation under reduced pressure to obtain thecorresponding diazoketone which as far as is known, is not described inthe literature.

The said diazoketone was suspended in 350 cc of 4-(2,2-dimethyl-1,3-dioxolane)-methanol and then a solution of 9 g ofsilver benzoate in 112.5 cc of triethylamine was added dropwise at 36 Cin 6 hours. The product gave off nitrogen and after cooling to 20 C, itwas added to water. The insoluble was removed by filtration and theinsoluble and the aqueous phase were reextracted with ether. The etherphase was washed with water, dried, treated with activated carbon whichwas filtered off and evaporated to dryness under reduced pressure. Theresidue was purified by passage over silica gel and elution with a 95:5mixture of methylene chloride and ether. The eluate was treated withactivated carbon and concentrated to dryness under reduced pressure toobtain 39.73 g of [4"(2, 2-dimethyl-1 ,3-dioxolane)] methyl3-pchlorobenzoylphenyl acetate melting at C.

Analysis: C H CIO molecular weight 388.83

Calculated:

As far as is known, this compound is not described in the literature.

STEP D: [4'-(2', 2-dimethyl-1,3-dioxolane)] methyla-(3-p-dhlorobenzoylphenyl) propionate 15 cc of a solution of 1.7 molesof butyllithium per liter of hexane was added over 20 minutes whilekeeping the temperature below 35 C to a mixture of 100 cc oftetrahydrofuran, 100 cc of hexamethyl phosphor triamide and 2.65 cc ofdiethylamine cooled to 40 C and the mixture was then stirred for 15minutes at -40 C. A solution of g of [4-(2', 2'-dimethyl-1',3-dioxolane)] methyl 3-p-chlorobenzoyl phenyl acetate in 60 cc oftetrahydrofuran was added thereto over minutes while keeping thetemperature below 35C and the mixture was then stirred for 15 minutes at40C. After the addition of 3.5 cc of methyl iodide, the mixture wasstirred for 30 minutes at 35C and then allowed to stand at C for 1 hour.The mixture was added to water and the aqueous phase was extracted withisopropyl ether. The ether phase was washed with water, dried andconcentrated to dryness under reduced pressure. The residue wasdissolved in ethyl ether and the solution was treated with activatedcarbon which are removed by filtration. The filtrate was evaporated todryness under reduced pressure to obtain 9.8g of [4'-(2',2-dimethyl-l',3-dioxolane)]- methyl a-(3-p-chlorobenzoyl phenyl)-propionateAnalysis: c,,H,,cio,-, molecular weight 402.87

Calculated: Found:

EXAMPLE ll PREPARATION OF 2,3'-dihydroxypropyla-(3-pchloro benzoylphenyl) propionate 6.97 g of [4'-(2',2-dimethyl-l', 3-dioxolane)] methyla-(3-p-chlorobenzoyl phenyl) propionate and 10.8 g of boric acid wereadded to 35 cc of methoxy ethanol and the reaction mixture was heated at100 C for 2 hours. The mixture was cooled to 10C and was filtered toremove the boric acid that precipitated and was washed with ether. Theorganic phase was washed with water, a saturated aqueoussodiumbicarbonate solution and with water and dried. The solution was treatedwith activated carbon and was concentrated to dryness by distillationunder reduced pressure to obtain 5.87 g of the2,3'-dihydroxy-propyla-(3-pchlorobenzoyl phenyl) propionate.

Analysis: Ci H,,ClO,; molecular weight 362.81

Calculated:

As far as is known, this compound is not described in the literature.

EXAMPLE Ill PREPARATION OF [4-(2,2-dimethyl-l',3- dioxolane)] methyl3-p-chlorobenzoylphenyl acetate STEP A:3-bromomethyl-4'-chlorobenzophenone A mixture of 68 g of m-toluic acidand 107.5g of phosphorus pentachloride was kept in contact for 15minutes and the phosporous oxychloride formed was distilled off underreduced pressure. Then 112.5 g of chlorobenzene were added thereto andthe mixture was heated to 90 to 100 C with stirring. Then, 66.75 g ofaluminum chloride were added to the mixture which was stirred for 2hours at 125-134C. After cooling to room temperature, 300 g of ice wereadded to the mixture which was then vacuum filtered. The recoveredprecipitate was empasted with water and dried under reduced pressure.The residue was crystallized from methanol, treated with activatedcarbon and dried under reduced pressure to obtain 67.1 g of 3-methyl-4'chlorobenzophenone melting at 108 C.

A mixture of 23.05 g of 3-methyl4- chlorobenzophenone, 70 cc of carbontetrachloride, 16.02 g of N-bromosuccinimide and 90 mg benzoyl peroxidewas refluxed for 4 hours and then was added to 100 cc of carbontetrachloride. The mixture was filtered hot and the filter was washedwith 100 cc of boiling carbon tetrachloride. 200 cc of the solvent wasdistilled off under reduced pressure and the mixture was cooled and icedfor 1 hour. The mixture was vacuum filtered and the recovered crystalswere empasted with iced carbon tetrachloride and dried under reducedpressure. The residue was crystallized from ethanol to obtain 17.5 g of3-bromomethyl-4 chlorobenophenone melting at l38l39C.

STEP B: 3-p-chlorobenzoylphenyl-acetonitrile A solution of 17g of3-bromomethyl-4- chlorobenzophenone in cc of dioxane at 70C was added tothe solution of 265g of potassium cyanide in 75 cc of water and themixture was refluxed with stirring for 6 hours. After cooling, 500 cc ofether was added to the mixture and the aqueous phase was decanted off.The organic phase was washed with water until the wash waters wereneutral, dried over magnesium sulfate, treated with activated carbon,filtered and evaporated to dryness under reduced pressure. The residuewas crystallized from methanol to obtain 9.61 g of 3-p-chlorobenzoylphenyl acetonitrile melting at 86 to 90 C.

STEP C: 3-p-chlorobenzoyl phenyl-acetic acid A mixture of 9.61 g of3-p-chlorobenzoyl phenyl acetonitrile, 75 cc of water, 75 cc of aceticacid and 75 cc of sulfuric acid was refluxed with stirring for 2 /2hours and then cooled and iced for 1 hour. The mixture was vacuumfiltered and the precipitate was empasted with water and taken up in 50cc of a l0percent aqueous sodium carbonate solution. The solution wasfiltered and the filter was washed with water. The pH of the filtratewas adjusted to 5-6 by addition of acetic acid and after being iced for30 minutes, the mixture was vacuum filtered. The recovered precipitatewas washed with water and dried under reduced pressure. The residue wasdissolved in 50 cc of refluxing toluene and the solution was treatedwith activated carbon and filtered. The filter was washed with boilingtoluene. The filtrate was cooled and iced for 1 hour and then vacuumfiltered. The recovered precipitate was empasted with iced toluene anddried under reduced pressure to obtain 8.37 g of 3-p-chlorobenzoylphenyl-acetic acid melting at 148 C.

STEP D: Methyl 3-p-chlorobenzoyl phenylacetate 10.3 g of3-p-chlorobenzoy1 phenylacetic acid were dissolved in 250 cc ofmethylene chloride and a solution of diazomethane in methylene chloridewas added thereto until there was a yellow coloration. The reactionmixture ,was stirred for 30 minutes and then a few drops of acetic acidwere added to destroy any excess diazomethane. The organic phase waswashed with iced 0.1N sodium hydroxide solution and then with wateruntil the wash waters were neutral, dried over sodium sulfate, treatedwith activated carbon, filtered and dried. The residue was empasted withisopropyl ether filtered and dried to obtain 7.5 g of methyl3-pchlorobenzoyl phenylacetate. The product occurred in the form of acolorless solid melting at 65 C and soluble in most of the usual organicsolvents and insoluble in water. Crystallization of the product fromisopropyl ether for analysis did not change the melting point.

Calculated: Found:

As far as is known, this compound is not described in the literature.

STEP E: [4'-(2',2-dimethyl-1',3-dioxolane)] methyl3-p-chlorobenzoyl-phenylacetate 40 cc of 4-(2,2-dimethyl-l ,3-dioxo1ane)methanol heated to 85 C was added to 0.20 g of a suspension of 50percent sodium hydride in vaseline oil and 5.774 g of methyl3-p-chlorobenzoyl-phenylacetate and the reaction mixture was stirred for3 hours at 85 C under a pressure of 30 mm Hg. The reaction mixture wasthen added to 100 cc of water containing a few drops of acetic acid andthe mixture was extracted with ether. The ether phase was dried overmagnesium sulfate and was evaporated to dryness under reduced pressure.The residue was subjected to chromatography over magnesium silicatetoobtain a 65 percent yield of [4'-(2',2'- dimethyl-l ,3 '-dioxolane)]methyl B-p-chlorobenzoylphenylacetate in the form of a crystallineproduct melting at 70 C. The product was soluble in methylene chloride,chloroform, methanol, acetone and ethyl ether.

Analysis: c,.H,.c1o,-, molecular Weight 388.85 Calculated: %c 64.87 %H5.44 %CI 9.11 Found: 64.6 5.4 9.4

The product was identical to that described in Step C of Example 1.

EXAMPLE 1V 5.231 g of boric acid and 17 cc of methoxyethanol was heatedat 100C for 45 minutes and after cooling, the mixture was vacuumfiltered. The filtrate was added to 200 cc of water and the mixture wasextracted with ether. The ether phase was washed with an aqueous sodiumbicarbonate solution, dried over magnesium sulfate and evaporated todryness under reduced pressure. The residue was empasted with isopropylether and thencrystallized from ethyl ether to obtain a percent yield of2,3'-dihydroxypropyl 3-p -chlorobenzoy1 phenyl acetate melting at 68 C.The colorless product was soluble in methylene chloride, chloroform,methanol, ethyl ether and acetone.

Analysis: C H ClOg, molecular weight 350.78

Calculated: %C 61.99 7cH 4.91 7rCl 10.17 Found: 61.8 4.9 10.5

I R Spectrum:

Presence of ester, conjugated ketone, aromatic substituted with aheteroatom and OH.

As far as is known, this product is not described in the literature.

EXAMPLE V Analysis: C H NCIO; molecular weight 179.60

Calculated: %C 60.19 Found: 60.0

As far as is known, this product is not described in the literature.

STEP B: 3-p-chlorobenzoyl-2-methyl-benzoic acid A solution of 95gof'p-bromochlorobenzene in 250 cc of ether was added to 15g of magnesiumin 250 cc of ether while maintaining the reaction mixture at reflux. Themixture was stirred for 1 hours at room temperature to obtain a solutioncontaining 0.78 mole per liter of p-chlorophenyl magnesium bromide.17.9g of cadmium chloride were added to 230 cc of the said solution andafter stirring for 10 minutes, the ether was distilled off whilemaintaining the volume constant by addition of benzene to obtain abenzene solution of bis- (p-chlorobenzene) cadmium compound.

The said benzene solution was cooled to 5C and then a solution of 27.4 gof 3-cyano-2-methyl-benzoyl chloride in cc of benzene was added thereto.The mixture was allowed to return to room temperature and was stirredovernight. The mixture was refluxed for 3% hours and after cooling, themixture was added to a solution of 30 cc of hydrochloric acid in 600 ccof water. The mixture was extracted with ether and the combin'ed etherphases were washed successively with 1N hydrochloric acid, water, 1Nsodium hydroxide and water until the wash waters were neutral. Theorganic phase was dried over magnesium sulfate and evaporated to drynessunder reduced pressure. The residue was empasted with 40 cc of petroleumether, vacuum filtered, washed with petroleum ether and dried at roomtemperature under reduced pressure to obtain 30.6 g of3-p-chlorobenzoyl-2-methyl-benzonitrile. For analysis, the product wascrystallized from methanol and melted at 84 C. The compound occurred inthe form of beige crystals soluble in methylene chloride and chloroform.

Analysis: C H NClO; molecular weight 255.70

Presence of C N at 2227 cm As far as is known, this compound is notdescribed in the literature.

STEP C: 3-p-chlorobenzoyl-Z-methyl-benzoic acid A mixture of 28 g of3-p-chlorobenzoyl-2-methylbenzonitrile, 210 cc of glacial acetic acid,210 cc of water and 210 cc of concentrated sulfuric acid was refluxedovernight and after cooling to 80 C, the reactionmixture was added to awaterice mixture. The mixture was vacuum filtered and the resultingprecipitate was washed with water until the wash waters were neutral andthen dried under reduced pressure to obtain 29.9g of3-p-chlorobenzoyl-2-methyl-benzoic acid melting at 205C. The product wassoluble in ethanol and chloroform and slightly soluble in ethyl ether.After crystallization from methanol for analysis, the product melted at206 C.

Analysis: C H O CI; molecular weight 274.69

Calculated: Found:

' IR Soectrum:

Absence of C N and presence of carbonyl at 1689 and 1672 cm" andaromatic.

As far as is known, this product is not described in .the literature.

A mixture of one-third of the said benzoyl chloride and cc of methylenechloride was cooled to 10 C and 300 cc of a methylene chloride solutioncontaining 12.15g per liter of diazomethane were added thereto.

The mixture was stirred overnight at room temperature and the methylenechloride was distilled off to obtain the corresponding diazoketonewhich, as far as is known, is not described in the literature.

The said diazoketone was dissolved in 100 cc of 4-(2,2-dimethyl-l,3-dioxolane)-methanol and then 7cc of a solution of lgof silver benzoate in 12.5 cc of triethylamine was added thereto insmall fractions with stirring at room temperature. After the evolutionof nitrogen eased, the reaction mixture was added to water and wasextracted with ether. The ether phase was washed with a saturatedaqueous sodium bicarbonate solution and then with water until the washwaters were neutral. The other solution was dried over magnesiumsulfate, treated with activated carbon, filtered and evaporated todryness under reduced pressure. The residue was purifiedby passage overmagnesium silicate and elution with ether. The solvent was evaporatedoff under reduced pressure to obtain 8.2g of [4'-(2,2- dimethyl-l',3-dioxolane)] methyl 3-p-chlorobenzoyl- Z-methyl-phenylacetate in theform of a pale yellow, amorphous product soluble in chloroform andmethanol and insoluble in water.

Analysis: C H CIO molecular weight 402.87

ii-Cl 8.80

Calculated: Found:

EXAMPLE VI 'PREPARATlON OF 2',3-dihydroxypropylchlorobenzoyl-2-methyl-phenylacetate A mixture of 7.6g of[4-(2,2-dimethyl-l '-,3- dioxolane)]-methyl 3-p-chlorobenzoyl-2-methy|-phenylacetate, 12g of boric acid and 54.5 cc of methoxy ethanol washeated at 100C for 1%. hours and then was cooled and filtered. Thefiltrate was added to 300 cc of water and the mixture was extracted withether. The ether extracts were washed with aqueous sodium bicarbonatesolution and then with water until the wash waters were neutral. Theether solution was then dried over magnesium sulfate and evaporated todryness under reduced pressure. The residue was purified by passagethrough magnesium silicate and elution with ether which was evaporatedoff under reduced pressure to obtain 5.63g of 2',3'-dihydroxypropyl3-pchlorobenzoyl-2-methyl-phenylacetate in the form of an amorphousyellow solid soluble in chloroform, ether and methanol and insoluble inwater.

Analysis: C H CIO molecular weight 362.8]

Calculated: Lo unil:

IR Spectrum: (Chloroform):

Presence of ester at 1741 of conjugated ketone at 1668"" and aromaticand OH.

As far as is known, this product is not described in the literature.

EXAMPLE Vll PREPARATION OF 3-p-chlorobenZoyl-2-methylbenzoic acid Asolution of 68g of p-chlorobromobenzene in 150 cc of ether was addedunder an inert atmosphere to 250 cc of a solution of 1.4N butyl lithiumin hexane cooled to C and after stirring for 2 hours, the temperaturewas allowed to rise to room temperature. A solution of 28.6g of3-cyano-2- methylbenzoic acid in 300 cc of tetrahydrofuran was added tothe solution of the lithium compound cooled to 60C and then thetemperature was allowed to return to room temperature and remain thereovernight. The reaction mixture was added to a water-ice mixture andmade acidic by addition of hydrochloric acid. The mixture was heated at7080C for 3 hours and the tetrahydrofuran was distilled off. Aftercooling, the mixture was extracted with ether and the ether phase waswashed with water, dried over magnesium sulfate and concentrated. Theresidue was empasted with isopropyl ether, vacuum filtered and dried.The residue was crystallized from methanol, and dissolved in methanoland treated with activated carbon, concentrated and allowed tocrystallize to obtain'10.3 g of 3-pchlorobenzoyl-2-methyl-benzoic acidmelting at 206C. A second crop of 4.3g of product was obtained bycrystallization of the mother liquors.

PHARMACOLOGICAL DATA Inflammation Test of the Paw of a Rat Caused byNaphthoylheparamine sion one hour before the irritant injection.

The degree of inflammation is estimated by plethysmometry with anelectric plethysmometric. The volume of the paw is expressed inarbitrary units. It is measured immediately before and two hours afterthe injection of naphthoylheparamine. The increase in paw volume betweenthe two measurements was the degree of inflammation. The degree ofaverage inflammation for each group is expressed in absolute values andas a per- TABLE A 2'.3'-dihydroxypropyl 3-p-ch1orobenzylabsrut a s Doseslncrease in Administered volume 7r of Lots in mg/kg of paw ProtectionControls 0 17.1 Treated 10 7.0 59 Controls 0 18.6 Treated 1 12.1 35

TABLE B 2,3-dihydroxypropyl 3-p-chlorobenzoyl-2-methyl- DhenvlacetuteDoses increase in Administered volume 7: of Lots in rng/kg of pawProtection Controls 0 18.1 Treated 2.5 9.8 46 5 7.1 61

TABLE C [4'-(2'.2'-dimethyl-l ,3-dioxolane)]-methyl3-pchlorobenzovl-2-methvl-phenvlacetate 2',3'-dihydroxy-propyla-(3-p-chlorobenzoyiphenyl)- gropionate Doses lncrease in Administeredvolume of of Lots in mg/kg paw Protection Controls 0 30.3 Treated 1 24.121

5 18.1 40 Control 0 22.4 Treated 10 10.6 53

' TABLE E [4-(2'.2'-dimethyl-l',3'-dioxolane)]-methyl agihlorg-bggzoylphgnyl l-propionate Doses Increase in Administered Volumeof of Lots in mg/kg paw Protection Control 0 26.1 Treated 1 20.4 22 515.1 42 10 10.0 61

The DA for 2',3-dihydroxypropyl 3-pchlorobenzoylphenylacetate is 1.5mg/kg, for

2',3'-dihydroxypropyl 3-p-chlorobenzoyl-2-methylphenylacetate is 2mg/kg, for [4'-(2',2'-dimethy1-l ',3 dioxolane)] methyl3-p-chlorobenzoyl-2-methylphenylacetate is 250 y/kg, and for2',3-dihydroxypropyl a-(3-p-chlorobenzoylphenyl)-propionate and for [4-(2',2'-dimethyl-1',3'-dioxolane)] methyl a-(3.-p-

chlorobenzoylphenyl)-propionate are mg/kg. These results show that the 5compounds have an important anti-inflammatory activity.

B. Analgesic Effect The test used was based on the fact noted by R.Koster et al (Fed. Proc., 1959, Vol. 18, page 412) wherein theintraperitoneal injection of acetic acid causes in mice characteristicrepeated stretching and twisting movements which can persist for morethan 6 hours. Analgesics prevent or suppress this syndrome which,therefore, can be considered as externalization of a diffuse abdominalpain.

A solution of 0.6 percent acetic acid in water containing percent arabicgum was used and the-dose which released the syndrome under theseconditions was 0.01 cc/gm, that is 60 mg/kg of acetic acid. The testcompounds were administered orally one-half hour before theintraperitoneal injection of acetic acid, the

mice having fasted since the night before the experi- TABLE AZ',3'-dihydroxyprogyl 3-! p-chlorobenzoyl l-phenylacetate DosesAdministered in mglkg of Protection TABLE B 2',3-dihydroxy-propyl3-p-chlorobenzoyl -2-methyltate Doses Administered in mg/kg ofProtection Douro- TABLE (3' [4'-(2',2'-dimethyl l',3'-dioxolane)] methyl3' Y i lacetate I 001i. Q [|l V Doses Adm n stered in m i of Protectionl 19 2 50 5 48 i0 66 20 83 5O 85 TABLE D 2'.3-dihydroxy-propyl a-( 3-p-chlorobenzoylphenyl)- Doses administered of protection so 'y/kg i6100 y/kg 29 200 'y/kg 53 TABLE D -COntinued 500 'y/kg 1 mg/kg ofprotection TABLE E Doses administered in mg/kg of protection The DA for2,3-dihydroxypropyl 3-pchlorobenzoylphenylacetate was 5 mg/kg, for2',3-dihydroxypropyl 3-p-chlorobenzoyl-2-methylphenylacetate and for[4'-(2',2'-dimethyl-l ',3- dioxolane)] methyl3-pchlorobenzoyl-2-methylphenylacetate is between 2 and 5 mg/kg, for2',3-dihydroxypropyl a-(3-p-chlorobenzoylphenyl)-propionate is very nearto 200 y/kg and for [4-(2',2'-dimethyl-l ,3'- dioxolane)] methyla-(3-p-chlorobenzoylphenyl)- propionate is between 1 and 2 mg/kg. Thefive compounds have an important analgesic activity.

C. Ulcerigenic activity The ulcergenic activity was determined by a testinspired by Boissier et al. [Ther. Vol. 22 (1967), P. 157] using femalerats 120-140 g which were starved for 24 hours before the start-of thetest. The products to be studied were orally administered as an aqueoussuspension at a volume of 0.4 cc per g of animal at varying doses. Theanimals were killed 7 hours after the treatment or 31 hours after thestart of the starvation and the stomachs were recovered. The importanceof the ulerous lesions were evaluated for each stomach, counting thenumber and size thereof. 2',3'-dihydroxypropyl3-p-chlorobenzoylphenylacetate did not provoke the formation of ulcersat a dose of 200 mg/kg and neither did 2',3 '-dihydroxypropyl3-p-chlorobenzoyl-2- methyl-phenylacetate at a dose of mg/kg. [4-(2',2'dimethyl-l ',3'- dioxolane)] methyl3-pchlorobenzoyl-2-methyl-phenylacetate did not provoke ulcers at a dosegreater than mg/kg and neither did 2 ,3 '-dihydroxypropyl a-(3-p-chlorobenzoylphenyl) propionate at a dose greater than 100 mg/kg nor[4' (2,2-dimethyl-l,3'-dioxolane)] methyl a-(3-pchlorobenzoylphenyl)propionate at a dose greater than 50 mg/kg.

Various modifications of the compositions and method of the inventionmay be made without departing from the spirit or scope thereof and it isto be understood that the invention is intended to be limited only asdefined in the appended claims.

We claim:

1. An anti-inflammatory and analgesic composition comprising aneffective amount of a compound of the group consisting of a racemate andan optically active isomer of a benzoylphenylacetic acid ester of theformula wherein R is selected from the group consisting of hydrogen andalkyl of l to 7 carbon atoms, R and R taken together are P and Q beingalkyl of l to 5 carbon atoms and the two benzene rings are optionallysubstituted with a member of the group consisting of chlorine, fluorine,bromine, trifluoromethyl and alkyl and alkoxy and alkylthio of l to 7carbon atoms in the alkyl portion and a pharmaceutical carrier.

2. A method of relieving pain and inflammation in a warm-blooded animalwhich comprises administering to a warm-blooded animal a safe andeffective amount of a compound of the group consisting of a racemate andan optically active isomer of a benzoylphenylacetic acid ester of theformula 0 Q H E 0111011:

wherein R is selected from the group consisting of hydrogen and alkyl ofl to 7 carbon atoms, R and R taken together are

2. A method of relieving pain and inflammation in a warm-blooded animalwhich comprises administering to a warm-blooded animal a safe andeffective amount of a compound of the group consisting of a racemate andan optically active isomer of a benzoylphenylacetic acid ester of theformula
 3. The method of claim 2 wherein the compound is(4''-(2'',2''-dimethyl-1'',3''-dioxalanyl)) methyl3-p-chlorobenzoylphenylacetate.
 4. The method of claim 2 wherein thecompound is (4''- (2'',2''-dimethyl-1'',3''-dioxalanyl)) methyl3-p-chlorobenzoyl-2-methyl-phenylacetate.
 5. The method of claim 2wherein the compound is (4''-(2'',2''-dimethyl-1'',3''-dioxalanyl))methyl Alpha -(3-p-chlorobenzoyl-phenyl)-propionate.